N,N-dimethyl-10-(3-quinuclidinyl)-2-phenothiazine sulfonamide (LM 24056): mode of action of its gastric antisecretory effect

Abstract

The inhibitory effect on gastric secretion of a phenothiazine molecule, N,N-dimethyl-10-(3-quinuclidinyl)-2-phenothiazine sulfonamide (LM 24056), was studied in dogs equipped with gastric fistula (GF) and Heidenhain denervated pouch (HP). LM 24056 was infused intravenously before exogenous stimulations started: the gastric stimulation ws obtained either by gastrin, by combination of gastrin + bethanechol (subthreshold dose) or by histamine. 1. On gastrin-stimulated secretion, preliminary infusion of LM 24056 results in a weak and non-significant reduction on GF acid secretion, while on HP, the inhibition is significant with 1 and 2 micrograms x kg-1 x h-1 of gastrin. The LM 24056 concentrations which produced 50% inhibition (IC50) of acid secretion is close to 0.5 mg x min-1. 2. LM 24056 exerts a strong inhibitory effect on combination gastrin + bethanechol-stimulated acid and pepsin secretions on GH and HP. IC50 is close to 0.25 mg x min-1. 3. LM 24056 is able to delay the histamine-stimulated acid secretion. There are some differences in the gastric inhibitory effects in relation to the moment of LM 24056 administration regarding exogenous stimulant: LM 24056 seems to be able to compete gastrin and to delay the normal histamine stimulation. The most important inhibitory effect is exerted on combination gastrin + bethanechol. LM 24056 could act as an antigastrinic substance.